Polyamines: the pivotal amines in influencing the tumor microenvironment

Abstract

Cellular proliferation, function and survival is reliant upon maintaining appropriate intracellular polyamine levels. Due to increased metabolic needs, cancer cells elevate their polyamine pools through coordinated metabolism and uptake. High levels of polyamines have been linked to more immunosuppressive tumor microenvironments (TME) as polyamines support the growth and function of many immunosuppressive cell types such as MDSCs, macrophages and regulatory T-cells. As cancer cells and other pro-tumorigenic cell types are highly dependent on polyamines for survival, pharmacological modulation of polyamine metabolism is a promising cancer therapeutic strategy. This review covers the roles of polyamines in various cell types of the TME including both immune and stromal cells, as well as how competition for nutrients, namely polyamine precursors, influences the cellular landscape of the TME. It also details the use of polyamines as biomarkers and the ways in which polyamine depletion can increase the immunogenicity of the TME and reprogram tumors to become more responsive to immunotherapy.

Keywords: Amino acid metabolism; Immunotherapy; Polyamine; Tumor microenvironment.

Fig. 1

Polyamine metabolism is intrinsically linked with arginine, glutamine and methionine metabolism. Arginine (ARG) is catabolized by arginase 1 (ARG1) to form ornithine (ORN). Ornithine then feeds into polyamine metabolism by being decarboxylated by ornithine decarboxylase (ODC) to form putrescine (PUT). PUT uses decarboxylated S-adenosylmethionine (dcSAM) as an aminopropyl donor to form spermidine (SPD). Methionine adenosyltransferase (MAT) acts on methionine (MET) to form S-adenosylmethionine (SAM), which is subsequently decarboxylated by S-adenosylmethionine decarboxylase (AMD1). dcSAM is also the aminopropyl donor for conversion of SPD into spermine (SPM). SPM and SPD can be acetylated by spermidine/spermine N¹-acetyltransferase (SSAT). N¹-acetylated spermine or spermidine (AcSPM, AcSPD) can either be exported from the cell or further oxidized by polyamine oxidase (PAOX) to form SPD and PUT, respectively. ORN can alternatively be converted to proline (PRO) by way of a pyrroline-5-carboxylate (P5C) intermediate formed by ornithine aminotransferase (OAT) activity. Within the mitochondria, ARG can be metabolized to ORN by arginase 2 (ARG2) or to nitric oxide (NO) and citrulline (CIT) by nitric oxide synthase (NOS). CIT can also be formed from ORN by ornithine transcarbamylase (OTC). Glutamine (GLN) is metabolized to glutamate (GLU) and can serve as an alternative precursor to ornithine through P5C as an intermediate. Figure created using BioRender.com

Fig. 2

Cells within the TME compete for available amino acids including arginine, ornithine, and glutamine. Amino acids support the proliferation, survival and activity of T-cells in the TME. Pro-inflammatory cytokines are secreted by M1 macrophages following arginine metabolism to nitric oxide. The uptake of amino acids in these cells is severely limited, however, due to competition from tumor and immunosuppressive cells. Tumor cells upregulate arginine, ornithine and glutamine uptake to support their polyamine pool and increase proliferation and survival. Cancer-associated fibroblasts (CAFs) use polyamines to support their deposition of extracellular matrix (ECM) by increasing proline and collagen synthesis as well as increasing matrix metalloproteinases (MMPs) to promote ECM remodeling. Endothelial cells upregulate amino acid and polyamine metabolism to support angiogenesis by increasing proliferation and expression of VEGF and MMPs. The proliferation and function of MDSCs and M2 macrophages are also dependent on polyamine synthesis. Tumor-promoting and immunosuppressive cells preferentially import arginine, ornithine and glutamine to increase polyamine synthesis and support their function thereby depleting pro-inflammatory cells of vital nutrients. Figure created using BioRender.com

Fig. 3

Influence of polyamine depletion on the tumor microenvironment. Depletion of polyamines from immunosuppressive tumor microenvironments can reprogram the microenvironment to a more immune-permissive phenotype. DFMO-mediated depletion of polyamines has been shown to repolarize immunosuppressive M2 macrophages into a more pro-inflammatory M1 phenotype (1). Polyamine depletion has also been shown to reduce MDSCs and TAMs while increasing the infiltration of inflammatory T-cells into the TME (2, 3). Efficacy of T-cells can be increased by TME polyamine depletion resulting in a decrease of exhausted T-cell phenotypes and increased PD-L1 expression on tumor cells (4, 5). Lastly, DFMO-treated tumors exhibit less neovasculature than untreated tumors indicating that polyamine depletion may be protective against metastasis [10, 126]. Figure created using BioRender.com